This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. FOXP3 is a member of the forkhead/winged-helix family of transcriptional regulators. Mutation of human FOXP3 causes "X-linked autoimmunity and allergic dysregulation" syndrome(XLAAD) or "Immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome" (IPEX), which is a fatal recessive disorder failing to develop CD4+CD25+ Tregs. In T cell lineage, FOXP3 mutation causes loss of Treg suppressor function. FOXP3 associates with NFAT, NF-kB, AML1/Runx-1 and ROR[unreadable][unreadable] to function as a negative regulator of gene transcription. Multiple domains of FOXP3 required for its homo-oligomerization and function as a transcriptional repressor were identified. We have characterized FOXP3 as an oligomeric component that is part of an even larger supramolecular complex in which FOXP3 interacts with histone acetyltransferase (HAT) TIP60 and class II histone deacetylases (HDAC) including HDAC7 and HDAC9 in CD4+CD25+ Tregs. FOXP3 may recruit these binding partners to chromatin transcription modification. A detailed molecular mechanism of how FOXP3 interacts with these partner molecules to modify the gene transcription is not available. Structural studies of the relevant complexes will provide important insight into its function mechanism and facilitate the development of small compound or peptide drugs for the cure of related diseases.